You Nan, Zheng Lu, Liu Weihui, Zhong Xiao, Wang Weiwei, Li Jing
Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
PLA Center of General Surgery, General Hospital of Chengdu Army Region, Chengdu, Sichuan 610083, P.R. China.
Oncol Rep. 2014 Apr;31(4):1911-20. doi: 10.3892/or.2014.3043. Epub 2014 Feb 20.
Recent findings suggest that clinical hepatocellular carcinoma (HCC) progression is driven by hepatic cancer stem cells (HCSCs) through their capacity for self-renewal, generation of heterogeneous lineages of cancer cells, resistance to chemotherapy and their ability to divide limitlessly, which may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, HCSC-directed therapeutic approaches might represent strategies to improve clinical HCC therapy. In previous studies, we showed that BC047440 was found to play a critical role in mediating HCC cell proliferation. The present study sought to determine whether BC047440 is involved in maintaining HCSC malignant behavior (including proliferation and differentiation). We demonstrated that BC047440 expression was markedly upregulated in HCSCs. Furthermore, we inhibited BC047440 in HCSCs using short hairpin RNA (shRNA). The effects of BC047440 on proliferation and differentiation were investigated. We also analyzed the involvement of critical molecular events known to regulate the proliferation and the differentiation machinery. Excluding apoptosis-related effects, we found that BC047440 inhibition resulted in enhanced cell proliferation through enhancing cytoplasmic accumulation of nuclear factor-κB (NF-κB) with a concomitant decrease in the nuclear fraction. BC047440 inhibition also resulted in inducing HCSC differentiation into hepatocytes. Furthermore, following downregulation of BC047440, the level of hepatocyte nuclear factor 4α (HNF4α) increased. Finally, tumorigenicity suppression following BC047440 depletion was confirmed in a nude mouse model. In conclusion, our findings indicate that BC047440 plays an important role in the proliferation and differentiation of HCSCs and may represent a novel therapeutic target for the treatment of HCC.
最近的研究结果表明，临床肝细胞癌（HCC）的进展是由肝癌干细胞（HCSCs）驱动的，这些干细胞具有自我更新能力、产生异质性癌细胞谱系的能力、对化疗的抗性以及无限分裂的能力，这可能是现有疗法无法持续根除恶性肿瘤的原因。因此，针对HCSC的治疗方法可能是改善临床HCC治疗的策略。在先前的研究中，我们发现BC047440在介导HCC细胞增殖中起关键作用。本研究旨在确定BC047440是否参与维持HCSC的恶性行为（包括增殖和分化）。我们证明BC047440在HCSCs中的表达明显上调。此外，我们使用短发夹RNA（shRNA）在HCSCs中抑制BC047440。研究了BC047440对增殖和分化的影响。我们还分析了已知调节增殖和分化机制的关键分子事件的参与情况。排除与凋亡相关的影响后，我们发现抑制BC047440可通过增强核因子κB（NF-κB）的细胞质积累并伴随核部分的减少来促进细胞增殖。抑制BC047440还导致诱导HCSC分化为肝细胞。此外，在下调BC047440后，肝细胞核因子4α（HNF4α）的水平升高。最后，在裸鼠模型中证实了BC047440缺失后对致瘤性的抑制作用。总之，我们的研究结果表明BC047440在HCSCs的增殖和分化中起重要作用，可能是治疗HCC的新治疗靶点。
